Renal failure patients often show alterations in drug disposition as compared to non-renal failure patients. These alterations are not always predictable which can cause problems in optimizing drug therapy in renal failure patients. This project will investigate the different mechanisms whereby drug disposition is altered in these patients. Pharmacokinetic studies will be performed in uremic and normal animals, in the presence and absence of infused drug metabolites. Liver and kindney perfusions will be carried out to localize and identify particular mechanisms for drug disposition alterations. Pharmacokinetic studies will also be performed in normal volunteers and in patients with decreased renal function under treatment with the investigated drugs. Total and unboud plasma concentrations and urinary excretion of drug metabolites will be determined simultaneously by testing the renal function. These studies outlined in the following proposal are designed to elucidate the disposition of drugs in renal failure, and to increase the ability to predict alterations in this disposition thereby improving the drug therapy in renal failure patients.